Soluble TAM receptor biomarkers: Neuroprotection in AD neuroinflammation?"

Abstract

AbstractBackgroundWhile neuroinflammation is reckoned as a pathological hallmark of AD, research on suitable biomarkers is still ongoing. Here, we report on findings from the DZNE DELCODE, Fundacío ACE and other cohorts demonstrating distinct inflammatory biomarker profiles in CSF and serum. Intriguingly, within these profiles, soluble TAM receptor markers are elevated in neurodegeneration but still relate to protection of cognition and brain structure.MethodWe investigated a panel of 20 experimental biomarkers utilizing customized immunoassays in CSF and serum samples of DELCODE and other cohorts with a total of >1000 subjects, including healthy controls, subjective cognitive decline, mild cognitive impairment, AD relatives and AD patients. Data were analyzed in relation to clinical and biomarker‐based staging as well as cognitive and structural imaging composite scores, adjusted for covariates such as age.ResultVarious inflammatory markers, when measured in CSF, were found to correlate to tau isoforms and other neurodegeneration markers and to be elevated in pre‐dementia stage subjects with already pathological tau levels. Among these, soluble TAM receptors sAXL and sTyro3 were related to preserved cognition and brain structure. In serum, inflammatory markers displayed different interrelations, with individual proteins in serum showing no or modest correlation to their CSF counterparts or other AD biomarkers. Noteworthy, serum soluble AXL increased only in AD subjects and related to decreased structure and function.ConclusionNeurodegeneration in AD is accompanied by a pattern of elevated inflammatory CSF biomarkers. These proteins likely represent cellular responses to neuronal damage and are evident already at pre‐dementia stages of disease. Within this response, upregulation of TAM receptors in the brain could serve to regulate neuroinflammation and promote cellular survival, with receptor turnover resulting in elevated CSF levels. Noteworthy, blood signatures of the same biomarkers, though not without significance, show different patterns of relations towards disease features, likely reflecting distinct peripheral cellular origins and biological functions of the respective proteins. These findings point towards TAM signalling as potential target for future therapeutic intervention, especially in subjects with pre‐dementia neurodegeneration phenotypes. As such, CSF soluble TAM levels might provide promising readout biomarkers.